6-chloro-delta3, 5-steroid derivatives and process for their manufacture



United States Patent ()fiice 3,301,875 6-CHLORO-A -STEROID DERIVATIVESAND PROCESS FOR THEIR MANUFACTURE Werner Fritsch, Neuenhain, Taunus,Werner Haede, Hofheim, Taunus, Heinrich Ruschig, Bad Soden, Taunus, andUlrich Stache, Hofheim, Taunus, Germany, assignors to Farhwerke HoechstAktiengesellschaft vormals Meister Lucius & Bruning, Frankfurt am Main,Germany, a corporation of Germany N Drawing. Filed Sept. 21, 1964,'Ser.No. 398,105 Claims priority, application Germany, Sept. 28, 1963,

40,866 13 Claims. (Cl. 260-3973) It is known (H. Gross and I. Gloede,Ber., 96 (1963), page 1384) that aryl-alkyl-ketones as Well as aliphaticand alicyclic ketones (for instance cyclohexanone) can be converted intothe corresponding vinyl-monochlorides (for instance intol-chloro-cyclohexene-l) by treating them with pyrocatechyl phosphoroustrichloride.

Now we have found a process for the manufacture of 6-chloro-A -steroidderivatives which comprises chlorinating 3,5-cyclo-6-oxo-androstanes,-pregnanes, -pregnenes or -oestranes in 6-position with a chlorinatingagent, preferably with pyrocatechyl-phosphorous-trichloride,hy-drolising in an acid medium ketal groups which may be present, andtreating the dichlorine derivative with agents splitting off hydrogenchloride, preferably with tertiary bases showing a high boiling point orwith alkali metal carbonates or alkaline earth metal carbonates indime-t'hylforrnamide.

The reaction takes the following course:

0 Ha CH3 O i l. P 015 /I3 Other keto groups which might be present inthe steroid molecule have to be suitably protected. It is particularlydesirable previously to convert them into the corresponding ke-tals,and, if a 17a,21-hydroxy-20-oxo side chain is present, into thecorresponding ethylene-dioxy derivatives. Hydroxyl groups that may bepresent can be protected by acylation.

In carrying out the process, the 3,5-cyclo-6-oxo-androstane, -pregnane,-pregnene or -oestrane derivative is dissolved in a solvent inert to thechlorinating agent, for instance, benzene, toluene, dioxane,tetrahydrofurane or ether, if necessary likewise in a mixture of saidsolvents, and 1 to 3 mol-equivalents of the chlorinating agent, such,for instance, as pyro-catechyl-phosphorous trichloride or a solutionthereof in one of the above-mentioned solvents is added, if necessary,with cooling. The reactants can likewise be reacted in their solidstate.

3,301,875 Patented Jan. 31, 1967 The reaction which, in most cases,occurs with evolution of heat, is carried out at temperatures betweenzero and 100 0., preferably between 40 and C. Generally, the reactionperiod varies between some minutes and several hours according to thetemperature applied.

For isolating the 3,6-dichloro-A -steroid derivatives obtained at first,the reaction mixture is stirred into a sufficient amount of water, ifthe solvents used are miscible with water. When solvents immiscible withwater are used, the reaction mixture is thoroughly shaken for some timewith water. The whole is then neutralized with bases, preferably withinorganic bases such as aqueous alkali metal bicarbonate solution,alkali metal carbonate solutions, alkali metal hydroxides or alkalineearth metal hydroxides. The dichloro-steroid present in the mixtures issubsequently extracted with suitable solvents, preferably with benzene,ether or methylene-chloride, washed with water and the organic phase isevaporated in dryness.

In the second phase of the process claimed, the 3,6 dichloro-A -steroidderivatives obtained are suitably treated for half an hour to 2 hourswith a tertiary base of the quinoline series having a high boilingpoint, advantageously with quinoline itself, at an elevated temperature,suitably at the reflux-temperature of the base used. In order to beworked up, the reaction mixture is taken up in an organic solvent,immiscible with water and washed with water and hydrochloric acid. Byconcentrating the solvent the crystalline product is obtained.

Another method for splitting off hydrogen chloride consists in that the3,6-dichloroA -steroid is reacted in dimethyl-formamide for half an hourto 2 hours at temperatures between 80 C. and the reflux-temperature ofthe dirnethyl-formamide with alkali metal carbonates or alkaline earthmetal carbonates, preferably lithium carbonate or likewise calciumcarbonate.

As starting substances for the process according to the presentinvention, the folowing compounds can be used:

17,B-acyloxy-6-oxo-3 ,5 -cyclo-an-drostanes, 173-acyloxy-17a-alkyl-6-oxo-3,S-cyclo-androstanes,l7/3-acetoxyl7a-methyl-6-oxo-3 ,5 -cyclo-androstane,17fl-a-cetoxy-l7u-alkyl-6-oxo-3,5 -cy-clo-androstanes,'l'io-acyloxyd7a-ethinyl-6-oxo-3 ,5 -cyclo-androstanes,20-ethylene-dioxy-6-oxo-3 ,5 ,-cyclo-pregnane,20-ethylene-dioxy-6-oxo-3,5 -cyclo-A -pre gnene, 17,20:20,21-bis-rnethylene-dioxy-6-oxo-3,5-cyclopregnane,17,20:20,21-bis-n1ethylene-dioxy-6-oxo-3,5-cyclo-A pregnene,17u-acyloxy-20-ethylene-dioxy-6-oxo-3,5 -cyclopregnanes,17-ethylene-bisoxy-6-oxo-3,S-cyclo-androstane,17-ethylene-bisoxy-6-oxo-3 ,5 ,cyclo-oestrane,17B-acyloxy-17a-ethinyl-6-oxo-3 ,5 -cyclo-oestranes, 17;3-acyloxy-17a-alkyl-6-oxo-3,S-cyclo-oestranes, l7a-acyloxy-6,20-dioxo-3 ,5 -cyclo-pregnanes, 17a-acyl0xy-16-methyl-6-oxo-3 ,5 -cyclo-pre gnanes,17a-acyl0xy-l6-methylene-6-oxo-3,S-cyclo-pregnanes,6,20-dioxo-3,5-cyclo-pregnane.

The above-mentioned 3,5-cyc1o compounds used as starting materials canbe obtained according to the process described by Julia et al., in Bull.Soc. Chim. (1960), pages 297-299, and the procedures disclosed in U.S.Patent 3,094,523.

The products obtained according to the process of the present invention,depending upon whether they belong to the androstaneor thepregnane-series, show anabolic or gestagenic action when orallyadministered. Moreover, they are interesting intermediate products forthe production of medicaments.

The following examples serve to illustrate the invention but they arenot intended to limit it thereto:

EXAMPLE 1 (a) 3,6-a'ichl0r0-A -andrstene-17-0ne 6.4 grams ofpyro-catechyl-phosphorus-trichloride are added to 4.5 grams of3,5-cyclo-6-oxo-l7-ethylene-dioxyandrostane with exclusion of humidity.The melt which forms with effervescence and heating is at firstabandoned for 30 minutes, heated then for minutes to 80 C. and afteraddition of 20 milliliters of anhydrous toluene to the reaction mixture,it is heated for a further minutes to 70 C. The reaction mixture is thenstirred into 100 milliliters of Water and, in order to achieve thesplitting of the ketal, the reaction mixture is shaken for 5 to 10minutes. Upon neutralization with aqueous bicarbonate solution it isextracted with benzene, washed with water, dried over sodium sulfate andconcentrated to dryness under reduced pressure. After recrystallizationfrom a a mixture of ether and methanol, 2.0 grams of 3,6-dichloro-A-androstene-17-one are obtained which melt at 177- 178 C.

(b) 6-chloro-A -androstadiene-1 7-0ne A solution of 4.6 grams of3,6-dichloro-A -androstene- 17-one in 100 milliliters of quinoline isheated to the boil for 70 minutes under nitrogen, with exclusion ofhumidity and with reflux.

50 milliliters of benzene are added to the cooled reaction mixture whichis washed until showing a neutral reaction successively by means ofhydrochloric acid, sodium-bicarbonate and water, dried over sodiumsulfate and evaporated to dryness under reduced pressure. Uponrecrystallization from a mixture of ether and petroleum ether 2.56 gramsof 6-chloro-A -androstadiene-17-one are obtained which melt at 145-146C. (Kofler heater).

(a) 3,6-dich Z0r0-A -pregnene-1 7 u-0l-20-0ne-1 7 -acetate 7.44 grams of3,5-cyclo-6-oxo-pregnane-l7a-ol-20-one- 17-acetate are dissolved in amixture of 100 milliliters of benzene and 10 milliliters ofmethylene-chloride and a solution of 5.9 grams ofpyro-catechyl-phosphorus-trichloride in 60 cc. of benzene is added inone portion at room temperature. After stirring for 3 hours at C. thereaction mixture is washed with water and diluted sodium bicarbonatesolution, dried over sodium sulfate and evaporated to dryness underreduced pressure. After recrystallization from methanol 2.5 grams of3,6-dichloro- M-pregnened7a-ol-20-one-17-acetate are obtained which meltat 825=9 C. (Kofler heater).

If, after a reaction period of 3 hours a moderate stream of dry hydrogenchloride is introduced for 15 minutes into the reaction mixture whilethe latter is cooled with ice, and the reaction mixture thus obtained isthen Washed with water and sodium bicarbonate solution until showing aneutral reaction, 8.1 grams of 3,6-di-chloro-Apregnene-17a-ol-20-one-17-acetate are obtaine" which melt at 258259 C.(Kofier heater).

(b) 6-chl0r0-A -pregnadiene-1 7a-0l-20-0ne-1 7-acetate A solution of1.24 grams of 3,6-dichloro-A -pregnene- 17a-o1-20-one-l7-acetate in 12.5milliliters of dimethylformamide is added under nitrogen to a boilingsuspension of 1.24 grams of lithium carbonate in 8.5 milliliters ofdimethyl-formamide and heated to the boil for 3 hours under reflux. Anyunreacted lithium carbonate is filtered 01f with suction in hot state,the mass is washed with a small amount of dimethyl-formamide and thefiltrate is crystallized by sprinkling it with water. The crystals arefiltered off, washed With water and recrystallized from a mixture ofmethylene-chloride and methanol. 880* milligrams of 6-chloro-A-pregnadiene-17ot-ol-20-one-17-acetate are obtained which melt at21'8219 C.

A max.=237.5; 244.3; 252 mu, s=19',90=0, 21,500, 13,100 (in methanol).

4. EXAMPLE 3 (a) 3,6-a'ichl0r0-A -pregnene-20-0ne 3 grams of3,S-cyclo-pregnane-6,20-dione are dissolved with 3 grams ofpyro-catechyl-p hosphorus trichloride in 3 cc. of benzene. Upon decay ofthe reaction, the reaction mixture is still heated for 5 minutes to 50C. 5 cc. of a solution of hydrochloric acid and glacial acetic acid of10% strength is then added and the whole is allowed to stand for 30'minutes at room temperature. The solution is then diluted by means ofmethylene chloride, shaken for a short period with cold diluted sodiumhydroxide solution, dried with Na SO and evaporated to dryness underreduced pressure. From methanol there are obtained 2.1 grams of3,6-dichl.oro-A -pregnane-20*-0ne of a melting point of 124 C.

(b) 6-chl0-ro-A -pregnadiene-20-0ne By treatment of 0.6 gram of3,6-dichl0r0-A -pregnene 20-one with lithium carbonate according to theconditions described in Example 2, there is obtained 0.21 gram of 6-chloro-A -pregnadiene-20-one of a melting point of 124 C. The mixedmelting point of the substance with the starting material gives adepression and is identified by analysis and infrared spectrum.

EXAMPLE 4 (a) 3,6-dichlor0-16-methylene-A -pregnene-17a-0l-20-one-acetate 4 grams of 3,5-cyclo-16-methylene-pregnane-17-m-ol-6,20-dione-acetate are mixed With 3.1 grams of pyrocatechylphosphorustrichloride and 3 cc. of benzene. Dissolution occurs with evolution ofheat. The mixture is then heated for 20 minutes to 60 C. and afteraddition of 4 cc. of a solution of hydrochloric acid and glacial aceticacid of 3% strength it is again heated for 1 hour to 35 C. The substanceis Worked up as described in Example 3.

Yield: 2.5 grams; melting point 237 C.

(b) 6-chlor0-1 6 -methy lens-A -pregnadiene-1 704-01-20- one-acetate Bytreatment of 1.8 grams of 3,6-dichloro-16-methylene-A-pregnene-17a-ol-20-one-acetate with lithium carbonate as described inExample 2, 1.4 grams of 6-chloro- 16-methylene-A-pregnadiene-17a-ol-20-one-actate is obtained. Melting point 188 C.

EXAMPLE 5 (a) 3,6-dichlor0-17a-ethinyl-A -andr0stene-17fi-0l-acetate 4grams of 17a-ethinyl-3,5-cyclo-androstane-17,B-ol-6- one-acetate areheated with 2.4 grams of pyro-cateohylphosphorus trichloride in 6 cc. ofbenzene for minutes to 60 C. Upon addition of 6 cc. of a solution ofhydrochloric acid and glacial acetic acid of 5% strength the mixture isagain heated for 90 minutes to 40 C. It is worked up as described inExample 3. From isopropyl ether there are obtained 1.7 grams of3,6-diCl1l0lO-17aethinyl A androstene 175-ol-acetate. Melting point C.

(b) 6-chlor0-17u-ethinyl-A -andr0stadiene-17fl-ol-acetate By treatmentof 0.3 gram of 3,6-dichloro-17a-ethinyl- A -androstene-17,8-0l-acetatewith lithium carbonate as described in Example 2, 0.13 gram of6-ChlOIO-170t-6t'hll1Yl- A -androstadiene-17B-ol-acetate is obtained.Melting point 158 C.

EXAMPLE 6 (a) 3,6-dichloro-17a-ethinyl-A -oeslrene-l 7fl-ol-acetaze 0.3gram of 17a-ethinyl-3,5-cyclo4oestrane-1773-01-6- one-acetate is heatedwith 0.2 6 gram of pyro-eatechyL phosphorus trichloride in 0.3 cc. ofbenzene for 20 minutes to 60 C. After addition of 0.3 cc. of a solutionof hydrochloric acid and glacial acetic acid .of 7% strength it is againheated for 1 hour to 4 C. After working up as described in Example 3 andcrystallization from methanol 0.14 gram of 3,6-dichloro-17a-ethinyl-Aoestrene-17fi-ol-acetate is obtained. Melting point: 160 C.

(b) 6-chl0r0-17a-ethinyl-A -0estradiene-17B-0l-acetate By treating 50milligrams of 3,6-dichloro-17a-ethinyl- A -oestrene-17B-ol-acetate withlithium carbonate as described in Example 2, there are obtained fromisopropylether 31 milligrams of 6-chloro-17a-ethinyl-A-oestradiene-17B-ol-acetate, which after having been recrystallized frommethanol melt at 181 C.

We claim:

1. Process for the manufacture of 6-chloro-A -steroid derivatives whichcomprises reacting a compound selected from the group consisting of3,S-cyclo-6-oXo-androstanes, 3,5 cyclo-6-oxo-pregnanes,3,5-cyclo-6-oxo-A -pregnenes or 3,5-cyclo-6-oxo-A -pregnenes and3,5-cyclo-6- oXo-oestranes With pyrocatechyl-phosphorus trichloride andsubsequently treating the 3,6-dich1oro derivatives thus obtained atelevated temperature with a high boiling tertiary base of the quinolineseries or with an alkali metal carbonate or alkaline earth metalcarbonate in dimethylformamide to split off hydrogen chloride.

2. Process for the manufacture of 6-ch1oro-A -steroid derivatives whichcomprises reacting a compound selected from the group consisting of3,5-cyclo-6-oxoandrostanes, 3,5 cyclo-6-oXo-pregnanes, 3,5-cyclo-6-oXo-A-pregnenes or 3,5-cyclo-6-ox0-A -pregnenes and 3,5-cyclo-6-oxo-oestranes with pyrocatechyl-phosphorus trichloride hydrolysing anyketal groups in an acid medium and subsequently treating the3,6-dichloro derivatives thus obtained at elevated temperature with ahigh boiling tertiary base of the quinoline series .or with an alkalimetal carbonate or alkaline earth metal carbonate in dimethylformamideto split 01f hydrogen chloride.

3. Process as claimed in claim 1 wherein the splitting off of hydrogenchloride is carried out by treatment with quinoline.

4. Process as claimed in claim 2 wherein the splitting off of hydrogenchloride is carried out by treatment with quinoline.

5. Process as claimed in claim 1 wherein the splitting ofi of hydrogenchloride is carried out by treatment with an alkali metal carbonate indimethyl-formamide.

6. Process as claimed in claim 2 wherein the splitting off of hydrogenchloride is carried out by treatment with an alkali metal carbonate indimethyl-formamide.

7. Process as claimed in claim 1 wherein the splitting oil of hydrogenchloride is carried out by treatment with an alkaline earth metalcarbonate in dimethyl-formarnide.

8. Process as claimed in claim 2 wherein the splitting oil of hydrogenchloride is carried out by treatment with an alkaline earth metalcarbonate in dimethyl-formamide.

9. Process as defined in claim 5 wherein the alkali metal carbonate islithium carbonate.

10. Process as defined in claim 6 wherein the alkali metal carbonate islithium carbonate.

11. 6-chloro-A -androstadiene-17-one.

12. 6 ohloro 17a ethinyl-A -androstadiene-17B-ol acetate.

13. 6 chloro 17a ethiny1-A -oestradiene-17fi3-o1 acetate.

No references cited.

LEWIS GOTTS, Primary Examiner.

ELBERT L. ROBERTS, Assistant Examiner.

1. PROCESS FOR THE MANUFACTURE OF 6-CHLORO-$3,5-STEROID DERIVATIVESWHICH COMPRISES REACTING A COMPOUND SELECTED FROM THE GROUP CONSISTINGOF 3,5-CYCLO-6-OXO-ANDROSTANES, 3,5-CYCLO-6-OXO-PREGNANES,3,5-CYCLO-6-OXO-$9(11)-PREGNENES OR 3,5-CYCLO-6-OXO-$16-PREGNENES AND3,5-CYCLO-6OXO-OESTRANES WITH PYROCATECHYL-PHOSPHORUS TRICHLORIDE ANDSUBSEQUENTLY TREATING THE 3,6-DICHLORO DERIVATIVES THUS OBTAINED ATELEVATED TEMPERATURE WITH A HIGH BOILING TERTIARY BASE OF THE QUINOLINESERIES OR WITH AN ALKALI METAL CARBONATE OR ALKALINE EARTH METALCARBONATE IN DIMETHYLFORMAMIDE TO SPLIT OFF HYDROGEN CHLORIDE. 11.6-CHLORO-$3,5-ANDROSTADIENE-17-ONE.